[unreadable] The Principal Investigator, Dr.Buggs, has a long-term goal of becoming an independent researcher in pediatric endocrinology. She is particularly interested in exploring the potential relationship between growth factors and GnRH signaling in the pituitary. GnRH when bound to its receptor activates a number of intracellular signaling pathways that are also activated by insulin and insulin like growth factor I (IGF-1). Insulin and IGF-1 receptors are expressed in the anterior pituitary, and insulin and IGF-1 augment GnRH-stimulated release of gonadotropins (LH and FSH) in the pituitary. It is unclear whether insulin or IGF-1 regulates pituitary gene expression directly. Dr.Buggs has recent evidence indicating that insulin together with GnRH modulates expression of the LH[unreadable] gene via the transcription factor Egr-1. These findings suggest that hyperinsulinism may impact disorders of puberty and reproduction at the level of the pituitary. [unreadable] In the first aim of this KO8 grant, the role of insulin and IGF-1 signaling in the pituitary will be investigated by breeding mice that express a "floxed" insulin receptor (IR) or IGF-1 receptor gene with mice that express Cre recombinase specifically in the gonadotroph. The effect of IR or IGF-1 receptor loss on pituitary gene expression and reproductive function will be assessed by a variety of physiologic measures. In the second aim, the mechanism of insulin signaling on LH[unreadable] gene expression will be further examined by investigating whether interactions between Egr-1 and the co-activators, CREB-binding protein (CBP) and p300, are important for mediating effects of GnRH and insulin. Using protein interaction assays, chromatin immunoprecipitation assays, and transfection studies, interactions between Egr-1 and CBP/p300 will be characterized and mapped in the context of GnRH and insulin-stimulated regulation of the LH[unreadable]gene. [unreadable] Dr. Radovick and Dr. Wondisford will mentor Dr. Buggs. The Chicago Center for Reproductive Research (CCRR) of the SCCPR U54 and the University of Chicago Diabetes Research and Training Center (DRTC) will also provide research resources. Dr. Buggs' future goal is to design basic science and translational research studies that will provide new insights for managing pubertal and reproductive disorders. [unreadable] [unreadable]